Endogenous opioid systems are increasingly recognized as important regulators of basal hedonic homeostasis and as significant factors mediating acute and chronic responses to multiple drugs in addition to opiates. Our previous work has emphasized the role of enkephalins, acting through mu opioid receptors in mediating the opioid component of basal hedonic tone. We propose to extend these studies to examine the role such systems play in controlling acute behavioral responses to cocaine, whether administered non-contingently or self-administered. The rewarding and reinforcing effects of cocaine will be studied in mu and delta opioid receptor null mice and in mice deficient in pro-enkephalin or B-endorphin using the conditioned place preference and operant self- administration paradigms. In addition to evaluating the acute effects of cocaine in such opioid-deficient mice, we will examine these mice for anomalies in sensitized motivational responses to repeated non-contingent cocaine administration and for propensity to reinstate drug-seeking following prolonged extinction of such behavior. The loci within the brain wherein these endogenous opioid-mediated phenomena originate will be explored by two parallel approaches focusing initially on the ventral pallidum and nucleus accumbens: 1) attempts to reverse phenotypes observed in opioid receptor null mice will be made by local, lentiviral-mediated, expression of the receptor and 2) evidence of changes in opioid peptide release in these structures during various stages of cocaine exposure will be explored using microdialysis combined with mass spectrometry.Project Narrative These studies will increase our understanding of the neurochemical underpinnings of relapse following prolonged abstinence. These are key issues for the development of effective medications to treat cocaine addiction and the information gleaned from these studies will likely generalize to other classes of abused substances.